This invention relates to an alprostadil alkyl ester-containing composition for external application.
Erectile dysfunction refers to a condition of the inability to achieve and maintain penile erection sufficient to complete satisfactory sexual intercourse. There are two major causes for the erectile dysfunction: psychogenic and organic causes. Previously, erectile dysfunction was thought to be of psychogenic origin. In these days, however, it is believed that most of erectile dysfunction comes from organic causes resulting from damage in nerve, blood vessel or hormone system, surgery, or drug administration.
Erectile dysfunction can be cured with surgical or pharmacological means. For the pharmacological treatment, some effective drugs are available, orally or locally. As oral drugs, yohimbine and trazodone have been used, but their clinical effect is not pronounced. Recently, sildenafil, a selective inhibitor of phosphodiesterase, has been introduced into the market as an oral drug. This new oral drug showed positive result in the treatment of erectile dysfunction. However, the oral administration of a drug accompanies systemic side effects inevitably, since the drug reaches the site of action after it is distributed throughout the whole body by the systemic circulation. Sildenafil also has some systemic side effects such as headache, flushing, indigestion and changes in vision, etc. Particularly, it may cause a serious side effect, if taken by patient medicated with organic nitrates, due to the possibility of dramatic drop in blood pressure. Therefore, a local treatment is the method of choice for the treatment of erectile dysfunction, since it is a local disorder. For this purpose, alprostadil (prostaglandin E1), papaverine, or phentolamine has been used. Among them, alprostadil is demonstrated to be the most effective drug for the local treatment of erectile dysfunction. Until now, intracavernous injection and transurethral pellet of alprostadil are commercially available in the market. However, the injection formulation needs a direct injection to the penis. Thus, patients may feel uncomfortable, and a pain or bleeding, or even infection on the injected site may occur. The transurethral pellet also has inconvenience in inserting into urethra, and burning sense on urethra or pain on penis may occur.
As mentioned above, alprostadil shows excellent pharmacological effect in the treatment of erectile dysfunction when applied locally. However, these two invasive methods, intracavernous injection and transurethral delivery, are only available as currently available dosage forms even though a topical preparation is more convenient to apply than those methods. This is due to two problems in the formulation of alprostadil as a topical preparation.
One is the instability of the drug in the conventional topical preparation which usually contains water in it. Like other prostaglandins, alprostadil is degraded easily to prostaglandin A1 or prostaglandin B1 in the presence of water. Examples of patents in relation to topical preparation are U.S. Pat. Nos. 5,194,670 and 5,681,850. However, as mentioned above, topical preparations disclosed in these patents are unstable due to water contained therein.
The other one is that the skin permeation rate of alprostadil itself is too low to achieve therapeutic drug concentration locally when applied topically.
As patents to overcome this problem, in U.S. Pat. No. 6,046,244, alkyl-2-(N,N-disubstituted amino)-alkanoate or (N,N-disubstituted amino)-alkanol alkanoate has been used as the skin permeation enhancer, and in U.S. Pat. No. 5,942,545, dioxolane, dioxane, or acetal. However, these enhancers are not commercially available and there are not sufficient information on the effects of these enhancers other than that as a skin permeation enhancer so far, since these are new materials. The present inventors had found that some pyrrolidones of pharmaceutical or cosmetic grade enhance the skin permeation of alprostadil, and filed a patent application for this invention (Korean Patent Application No. 99-31090). The excellent skin permeation of alprostadil was obtained with the preparation of this patent. Also, the stability of alprostadil in the preparation was highly improved, since the topical formulation in this patent is based on non-aqueous vehicles. However, the preparation in this patent has also a shortcoming of severe topical irritation on the applied area, which may be due to the drug itself or the excipients used or the combination of the two. To overcome this problem, there has been studied for novel preparation containing anti-irritant agent by the inventors. As a result, the inventors have found out a composition which has excellent skin permeation rate with little skin irritation (Korean Patent Application No. 2000-34767).
The rate of skin permeation of alprostadil ethyl ester from the toical preparation in Example 3 were determined using Franz diffusion cell fitted with excised guinea pig skin. A topical preparation containing alprostadil prepared according to Example 3 in Korean Patent Application No. 2000-34767, that is, comparative example 1, was used as a reference. The effective diffusion area was 1.77 cm2. The receptor compartment of the diffusion cell was filled with 0.01 M phosphate buffer (pH 7.4) and its temperature was maintained at 37+0.5xc2x0 C. and stirred at 600 rpm during the experiment. The amount of alprostadil permeated into the receptor medium was determined with an HPLC method.
Prodrug means a compound that can be chemically transformed during or after absorption through skin, thereby to yield a parent drug, a pharmacologically active compound, via hydrolysis or enzymatic reaction. Generally, prodrug is obtained by transforming physical properties of the drug to enhance membrane permeation rate. A major method to synthesize the prodrug is to convert the drug into a modified form which is easily reactive on esterase which is widely distributed throughout the whole body.
It is reported that carboxyl group of alprostadil can be esterified to form a chain of alkyl group and that when chain length increases, permeation is enhanced by more than 10 times (Ho, H. O. et al. J. Control. Release 1999). Alprostadil alkyl esters having longer alkyl chain length are highly lipophilic and thus are easier to permeate stratum comeum, thereby exhibiting the above effect. And, during skin permeation, the prodrug is decomposed to alprostadil by esterase which is abundant beneath skin.
U.S. Pat. Nos. 5,219,885 and 5,380,760 disclose topical preparation of alprostadil alkyl ester. However, because topical preparation in U.S. Pat. No. 5,219,885 contains water, there is a drawback that alprostadil alkyl ester is easily hydrolyzed in the preparation. On the other hand, because topical preparation in U.S. Pat. No. 5,380,760 is in form of plaster obtained by dispersing drug in pressure sensitive adhesive, it is difficult to apply on the desired site.
The present inventors discovered a topical preparation containing alprostadil alkyl ester, obtained by dissolving alprostadil alkyl ester as a prodrug into an mixture of oily vehicles, skin permeation enhancers and anti-irritant agents, whose skin permeation is excellent compared to the conventional composition containing alprostadil, thereby to complete the present invention.
Therefore, an object of the present invention is to provide a composition of topical preparation containing alprostadil alkyl ester for the treatment of erectile dysfunction, which has not only excellent skin permeation rate but also is chemically stable.